KETOROLAC.RTM. or 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, the formula of which is: ##STR1##
has been known for several years (U.S. Pat. No. 4,089,969) and is used in human therapy as an analgesic and an anti-inflammatory.
Both the racemic form and each of the dextro and levo isomers of this compound are known. Many pharmaceutically acceptable salts, the most commonly used of which is the tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol) salt, are also known. Hereinafter, the name KETOROLAC.RTM. shall encompass individually or collectively the racemic mixture or either optically active compound and shall encompass the free acid as well as the tromethamine salt or any other pharmaceutically acceptable salt of any one of the foregoing.
Ample literature is available on KETOROLAC.RTM. (for instance, "KETOROLAC.RTM.--A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic potential", Drugs 39(1): 86-109, 1990. It is described as a drug with considerably higher analgesic and anti-inflammatory activity than many other non-steroid anti-inflammatory drugs. Most significantly, it has higher analgesic activity than morphine, without the well-known side effects of the latter.
In the several pharmacological and clinical trials involving KETOROLAC.RTM. that have been conducted, this drug was administered both by the oral route and by injection (in turn, both intravenous and intramuscular). Regardless of the administration route, KETOROLAC.RTM. proved active and was found comparatively more active than the better known non-steroid drugs with analgesic and anti-inflammatory activity. However, about 10% of the patients treated (20 doses of 30 mg each administered over five days) by the intramuscular route suffered from one or more undesirable side effects such as somnolence, local (injection site) pain, sweating, nausea, headache, dizziness, vomiting, pruritus, and vasodilation.
The incidence of side effects was even higher (around 32%) in the patients treated with KETOROLAC.RTM. by the oral route for a few days. In the case of oral administration, gastrointestinal disorders (nausea, g.i. pain, dyspepsia, diarrhea, flatulence, g.i. fullness, vomiting) were noted in up to 50% of the patients in addition to side effects incident to i.m. administration.
Intravenous administration is inconvenient and is limited to the treatment of acute conditions.
On the whole, the data available to date clearly describe a drug which is very active, but still unsatisfactory from the point of view of convenience of administration and/or side effects.